scholarly journals ABL1 Is a Prognostic Marker and Associated with Immune Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Rongqiang Liu ◽  
Weihao Kong ◽  
ZeKun Jiang ◽  
Shiyang Zheng ◽  
Xiaofeng Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Disease Free Survival ◽  
Protein Translation ◽  
Mitochondrial Activity ◽  
Nonalcoholic Fatty Liver ◽  
Immune Infiltration

Background. The role of ABL1 in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the potential role of ABL1 in the progression of HCC using bioinformatics methods. Methods. We analyzed the expression, prognostic potential, and immune cell effect of ABL1 in HCC by using a variety of datasets. Results. ABL1 is highly expressed in HCC and associated with unfavorable overall survival (OS) and disease-free survival (DFS). Functional network analysis revealed that ABL1 plays an important role in mitochondrial activity, ATP metabolism, protein translation and metabolism, various neurological diseases, nonalcoholic fatty liver disease, and notch signaling pathway. In addition, we found that ABL1 expression was closely correlated with B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, ABL1 expression was positively associated with the expression levels of immune checkpoint genes, such as PD-1L, TIM3, TIGIT, and CTLA4. Conclusion. ABL1 is associated with immune infiltration and prognosis of HCC.

scholarly journals CDCA3 Is a Novel Prognostic Biomarker Associated with Immune Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Zhihuai Wang ◽  
Shuai Chen ◽  
Gaochao Wang ◽  
Sun Li ◽  
Xihu Qin
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cell ◽  
Disease Free Survival ◽  
In Silico Analysis ◽  
Gene Markers ◽  
Free Survival ◽  
Immune Infiltration ◽  
Normal Tissues ◽  
Tumor Tissues

Cell division cycle-associated protein-3 (CDCA3) contributes to the regulation of the cell cycle. CDCA3 plays an important role in the carcinogenesis of various cancers; however, the association between CDCA3 expression, prognosis of patients, and immune infiltration in the tumor microenvironment is still unknown. Here, we demonstrated that CDCA3 was differentially expressed between the tumor tissues and corresponding normal tissues using in silico analysis in the ONCOMINE and Tumor Immune Estimation Resource (TIMER) databases. We analyzed the relationship between the expression of CDCA3 and prognosis of patients with hepatocellular carcinoma (HCC) using the Kaplan–Meier plotter database and Gene Expression Profiling Interactive Analysis (GEPIA). Furthermore, we determined the prognostic value of CDCA3 expression using univariate and multivariate analyses. We observed that CDCA3 expression closely correlated with immune infiltration and gene markers of infiltrating immune cells in the TIMER database. CDCA3 was highly expressed in the tumor tissues than in the adjacent normal tissues in various cancers, including HCC. Increased expression of CDCA3 was accompanied by poorer overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). The correlation between CDCA3 expression and OS and disease-free survival (DFS) was also studied using GEPIA. CDCA3 expression was associated with the levels of immune cell infiltration and was positively correlated with tumor purity. Moreover, CDCA3 expression was associated with gene markers such as PD-1, CTLA4, LAG3, and TIM-3 from exhausted T cells, CD3D, CD3E, and CD2 from T cells, and TGFB1 and CCR8 located on the surface of Tregs. Thus, we demonstrated that CDCA3 may be a potential target and biomarker for the management and diagnosis of HCC.

scholarly journals Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Petra Hirsova ◽  
Adebowale O. Bamidele ◽  
Haiguang Wang ◽  
Davide Povero ◽  
Xavier S. Revelo
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Nonalcoholic Steatohepatitis ◽  
Immune Cell ◽  
Current Knowledge ◽  
Significant Proportion ◽  
Nonalcoholic Fatty Liver ◽  
Integral Role

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

scholarly journals CDKN2A is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Jun-peng Luo ◽  
Jing Wang ◽  
Jin-hua Huang
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Cyclin Dependent Kinase ◽  
Strong Correlations ◽  
Immune Infiltration ◽  
Cyclin Dependent Kinase Inhibitor

Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is an essential regulator of immune cell functionality, but the mechanisms whereby it drives immune infiltration in hepatocellular carcinoma (HCC) remain unclear. In the current study, we studied the association with CDKN2A expression and immune invasion with the risk of developing HCC. A totally of 2207 different genes were found between HCC and adjacent liver tissues from TCGA and GEO databases. CDKN2A was highly expressed in HCC and associated with poorer overall survival and disease-free survival. Notably, CDKN2A expression was positively correlated with infiltrating levels into purity, B cell, CD+8 T cell, CD+4 T cell, macrophage, neutrophil, and dendritic cells in HCC. CDKN2A expression showed strong correlations between diverse immune marker sets in HCC. These findings suggest that CDKN2A expression potentially contributes to regulation of tumor-associated macrophages and can be used as a prognostic biomarker for determining prognosis and immune infiltration in HCC.

scholarly journals Positive Immuno-Modulation Following Radiofrequency Assisted Liver Resection in Hepatocellular Carcinoma

2019 ◽  
Vol 8 (3) ◽  
pp. 385 ◽  
Author(s):  
Kai Wen Huang ◽  
Kumar Jayant ◽  
Po-Huang Lee ◽  
Po-chih Yang ◽  
Chih-Yang Hsiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Liver Resection ◽  
Immune Cell ◽  
Disease Free Survival ◽  
Treg Cells ◽  
Chi Square ◽  
Immunological Parameters ◽  
Exact Test ◽  
Liver Resections

Introduction: Hepatocellular carcinoma (HCC) often develops on a background of chronic inflammation and a complex immunosuppressive network with increased regulatory T cells, impaired CD8+ T cells and the secretion of immunosuppressive cytokines. Previous clinical studies have reported a superior disease-free survival (DFS) following a radiofrequency-based ablation or resection in HCC tumours compared to conventional liver resection techniques. The aim of this study was to investigate whether there is any correlation with the use of a radiofrequency-assisted liver resection and clinical outcome. Material and Methods: Patients’ peripheral blood was collected prior and 7 days following surgery from patients undergoing a liver resection for HCC. There were 5 liver resections performed using CUSA and 6 liver resections with the RF-based device, HabibTM 4X. The primary endpoint of the study was to assess the immunological parameters of circulating immune cell populations as well as serum cytokines. The Student’s t-test, chi-square or Fisher’s Exact test were applied for statistical comparisons, as appropriate. Results: Patients undergoing an RF-assisted liver resection with HabibTM 4X had a significant decrease in the inhibitory Treg cells (p = 0.002) and a significant increase in CD8+ T lymphocytes (p = 0.050) and CD4+CD45RO+/CD4+ memory T cells (p = 0.002) compared to those patients undergoing a liver resection with CUSA. It was also noted that the RF-assisted liver resection group had a significant decrease in circulating TGF-ß (p = 0.000), IL10 (p = 0.000) and a significant increase in IFN-gamma (p = 0. 027) and IL-17 compared to the CUSA group. Conclusion: A liver resection with RF-based device HabibTM 4X was associated with positive immunomodulatory changes in circulating immune cells and circulating cytokines which could explain the significant improvement in DFS.

scholarly journals SPP1 is a Prognostic Related Biomarker and Correlated with Tumor-Infiltrating Immune Cells in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Xiaofeng Wang ◽  
Kun Zhang ◽  
Li Geng ◽  
DongLi Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Tumor Promoter ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
Secreted Phosphoprotein 1

Abstract Background: Secreted phosphoprotein 1 (SPP1) functions as a tumor promoter in varies tumors, but little is known whether it is an actual player on driving immune infiltration in hepatocellular carcinoma. Methods: In this study, we identified the expression of SPP1 by Oncomine, GEPIA and TIMER databases, and assessed SPP1 immumohistochemical staining analysis by The HPA database. We evaluated the clinical outcomes between SPP1 expression and hepatocellular carcinoma patients via Kaplan-Meier Plotter. We also tested the relationship between SPP1 and critical oncogenes by TIMER and GEPIA databases. Then we explored immune infiltration analyses using TIMER and TISIDB datasets. In addition, we performed functional enrichment analyses with Metascape and GeneMANIA databases. Results: We found that SPP1 overexpressed in hepatocellular carcinoma tissues and high SPP1 expression was correlated with shorter OS and PFS survivals in hepatocellular carcinoma patients. SPP1 expression is positive correlation with critical oncogenes related stemness associated genes, cell cycle and proliferation, therapeutic resistance, metastasis, and tumor angiogenesis in hepatocellular carcinoma. Importantly, SPP1 expression was positively correlated with infiltrating levels of CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression showed strong correlations with diverse immune hallmark sets in hepatocellular carcinoma. Notably, functional enrichment analysis suggested that SPP1 strong related with immune response. Conclusions: These findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in hepatocellular carcinoma.

scholarly journals Identification of Prognostic Biomarkers and Correlation With Immune Infiltrates in Hepatocellular Carcinoma Based on a Competing Endogenous RNA Network

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhangya Pu ◽  
Yuanyuan Zhu ◽  
Xiaofang Wang ◽  
Yun Zhong ◽  
Fang Peng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Survival Analysis ◽  
Immune Cell ◽  
Cox Regression ◽  
Quantitative Polymerase Chain Reaction ◽  
Prognostic Biomarkers ◽  
Hub Genes ◽  
Immune Infiltration ◽  
Cerna Network

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Recently, competing endogenous RNAs (ceRNA) have revealed a significant role in the progression of HCC. Herein, we aimed to construct a ceRNA network to identify potential biomarkers and illustrate its correlation with immune infiltration in HCC.MethodsRNA sequencing data and clinical traits of HCC patients were downloaded from TCGA. The limma R package was used to identify differentially expressed (DE) RNAs. The predicted prognostic model was established using univariate and multivariate Cox regression. A K-M curve, TISIDB and GEPIA website were utilized for survival analysis. Functional annotation was determined using Enrichr and Reactome. Protein-to-protein network analysis was implemented using SRTNG and Cytoscape. Hub gene expression was validated by quantitative polymerase chain reaction, Oncomine and the Hunan Protein Atlas database. Immune infiltration was analyzed by TIMMER, and Drugbank was exploited to identify bioactive compounds.ResultsThe predicted model that was established revealed significant efficacy with 3- and 5-years of the area under ROC at 0.804 and 0.744, respectively. Eleven DEmiRNAs were screened out by a K-M survival analysis. Then, we constructed a ceRNA network, including 56 DElncRNAs, 6 DEmiRNAs, and 28 DEmRNAs. The 28 DEmRNAs were enriched in cancer-related pathways, for example, the TNF signaling pathway. Moreover, six hub genes, CEP55, DEPDC1, KIF23, CLSPN, MYBL2, and RACGAP1, were all overexpressed in HCC tissues and independently correlated with survival rate. Furthermore, expression of hub genes was related to immune cell infiltration in HCC, including B cells, CD8+ T cells, CD4+ T cells, monocytes, macrophages, neutrophils, and dendritic cells.ConclusionThe findings from this study demonstrate that CEP55, DEPDC1, KIF23, CLSPN, MYBL2, and RACGAP1 are closely associated with prognosis and immune infiltration, representing potential therapeutic targets or prognostic biomarkers in HCC.

scholarly journals CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Yinjiang Zhang ◽  
Hongyun Wei ◽  
Lu Fan ◽  
Mingyan Fang ◽  
Xu He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Potential Role ◽  
Immune Cell ◽  
Mrna Level ◽  
Cell Activity ◽  
Expression Level ◽  
Cell Trafficking

Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

scholarly journals Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis

2021 ◽  
Vol 37 (3) ◽  
Author(s):  
Yusra Shafique ◽  
Muhammad Asif Qureshi ◽  
Saeed Khan ◽  
Talat Mirza
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cd4 T Cells ◽  
Potential Role ◽  
Immune Cell ◽  
P Value

Objectives: To investigate immune cell densities in tumor microenvironment of hepatocellular carcinoma. Methods: This cross-sectional study was conducted during 2017-2019 at the Dow University of Health Sciences Karachi. A total of 42 subsequent patients undergoing liver biopsy/resection and diagnosed with hepatocellular carcinoma were included in the study. Moreover, a total of 10 control tissues were also included. In order to investigate immune cells densities in hepatocellular carcinoma, immunohistochemistry was performed using antibodies including α-MPO(neutrophils), α-CD-68(macrophages), α-CD-3(T-cells), α-CD-20(B-cells), α-CD-4(CD4+ T-cells) and α-CD-8(CD8+ T-cells). Quantification of immune cells/mm2 was performed as per the College of American Pathologists’ guidelines. Data were analyzed using SPSS version 21. A p-value of 0.05 was considered significant at all times. Results: We report significantly increased infiltration of macrophages (mean macrophages= 306.57/mm2, p-value<0.05), moderately significant infiltration of neutrophils (p-value=0.06) and B-cells (p-value=0.07) while no significant infiltration of CD4+T-cells (p- value=0.31), and CD8+T-cells (p-value=0.39) in tumour microenvironment of patients with hepatocellular carcinoma. Conclusion: We provide evidence for increased macrophage infiltration in liver cancer microenvironment suggesting a potential role of these cells in hepatocarcinogenesis. doi: https://doi.org/10.12669/pjms.37.3.2973 How to cite this:Shafique Y, Qureshi MA, Khan S, Mirza T. Differential Immune Landscape of Hepatocellular Carcinoma Suggests Potential role of Macrophages in Hepatocarcinogenesis. Pak J Med Sci. 2021;37(3):---------. doi: https://doi.org/10.12669/pjms.37.3.2973 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

scholarly journals The bioinformatics and experimental analysis of AlkB family for prognosis and immune cell infiltration in hepatocellular carcinoma

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12123
Author(s):  
Bi Peng ◽  
Yuanliang Yan ◽  
Zhijie Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Metal Ion ◽  
Immune Cell ◽  
Disease Free Survival ◽  
Normal Liver ◽  
Expression Levels ◽  
Normal Tissues ◽  
Molecular Profiles

Background Serving as N6-methyladenosine demethylases, the AlkB family is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the molecular profiles and clinical values of the AlkB family in HCC are not well known. Methods Several bioinformatics tools and in vitro experiments were used to identify the immune-related profiles and prognostic values of AlkB family in HCC. Results In this study expression levels of ALKBH1/2/3/4/7 were all remarkably increased in HCC tissues when compared with normal tissues. Quantitative PCR (qPCR) and immunohistochemistry were used to validate the expression of AlkB family members in HCC tissues and normal liver tissues. In addition, high expression levels of ALKBH4 were negatively correlated with overall survival (OS) and disease-free survival (DFS) in patients with HCC. Increased ALKBH4 was also associated with pathological stage in HCC patients. The molecular profiles of AlkB family in HCC were mainly associated with peptidyl-serine modification, peptidyl-tyrosine modification, regulation of metal ion transport, etc. Furthermore, tumor-infiltrating immune cell analysis indicated that ALKBH1/2/3/4/5/6/7/8 and FTO were related to the infiltration of different immune cell, such as CD8+ T cells, macrophages, neutrophils, dendritic cells and CD4+ T cells. We also discovered that the methylation levels of ALKBH1/2/4/5/6/8 and FTO were remarkably reduced in HCC tissues. Conclusions Collectively, our findings may deepen the understanding of specific molecular profiles of the AlkB family in HCC pathology. In particular, ALKBH4 could serve as a promising prognostic candidate for treating HCC, and these results might potentiate the development of more reliable therapeutic strategies for patients with HCC.

scholarly journals TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuchuan Jiang ◽  
Siliang Chen ◽  
Qiang Li ◽  
Junjie Liang ◽  
Weida Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
T Cells ◽  
Cd8 T Cells ◽  
Prognostic Value ◽  
Immune Cell ◽  
Poor Prognostic Factor ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

BackgroundNumerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear.MethodsThe expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated via analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist.ResultsThe level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, P=0.038; Kaplan–Meier plotter: HR=1.87, P&lt;0.001; CPTAC: HR=2.23, P=0.007; Our cohort: HR=2.92, P=0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8+ T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. In vivo experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells.ConclusionsThe up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC.

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